The aminobenzenesulfonic acid derivatives represented by the following formula (I): ##STR2## wherein R.sup.1 represents a hydrogen atom, a C.sub.1 -C.sub.6 alkyl group, a C.sub.3 -C.sub.7 cycloalkyl group, a halogenated C.sub.1 -C.sub.4 alkyl group, a halogen atom, or a C.sub.6 -C.sub.12 aryl group; R.sup.2 represents a hydrogen atom, a C.sub.1 -C.sub.6 alkyl group, or a C.sub.7 -C.sub.12 aralkyl group which may have one or more substituents selected from the group consisting of cyano group, nitro group, a C.sub.1 -C.sub.6 alkoxy group, a halogen atom, a C.sub.1 -C.sub.6 alkyl group, and amino group; and n represents an integer of from 1 to 4, are known to have inhibitory activities on intracellular hyperaccumulation of Ca.sup.2+ (the Japanese Patent Unexamined Publication (KOKAI) No. (Hei)3-7263/1991). It has been also revealed that these compound are useful for the preventive and therapeutic treatment of ischemic heart diseases such as myocardial infarction or angina pectoris, cardiac failure, hypertension, arrhythmia and the like [the Japanese Patent Unexamined Publication (KOKAI) Nos. (Hei)3-7263/1991 and (Hei)4-139127/1992].
Among these compounds, 2-(1-piperazinyl)-5-methylbenzenesulfonic acid (the substance disclosed in Example 1 of the Japanese Patent Unexamined Publication (KOKAI) No. (Hei)3-7263/1991 and disclosed as Compound No. 12 in Preparation Example 1 of the Japanese Patent Unexamined Publication (KOKAI) No. (Hei)4-139127/1992) remarkably inhibits the inflow of calcium ions into cardiac muscle cells and is highly safe, and thus the compound is expected to be extremely useful as an active ingredient of a medicament for preventive and therapeutic treatment of heart diseases.
The methods for preparation of these compounds are disclosed in the Japanese Patent Publication (KOKOKU) No. (Hei)6-86438/1994, and according to these methods, the compounds of the above formula (I) are obtained as anhydrous crystals. However, according to the research by the inventors of the present invention, it was found that these anhydrous crystals are hygroscopic and may finally form monohydrates, when being left alone, by gradually absorbing moisture to gain weight. When the inventors conducted research particularly focusing on the preparation of formulations to provide 2-(1-piperazinyl)-5-methylbenzenesulfonic acid as a medicament for therapeutic and preventive treatment of heart disease, they faced problems that the substance could not be accurately weighed because it gradually absorbed moisture and varied in weight during manufacturing processes, and that constant formulations could not be stably manufactured because the contents of the active ingredient fluctuated from lot to lot of resulting formulations. In order to provide medicaments comprising the aforementioned aminobenzenesulfonic acid derivatives as active ingredients, it is thus desired that monohydrates instead of anhydrous crystals are used from the viewpoints of manufacturing and distributing medicaments being stable and having guaranteed constant qualities.
The Japanese Patent Unexamined Publication (KOKAI) Nos. (Hei) 3-7263/1991 and (Hei)4-139127/1992 disclose the presence of acid addition salts and base addition salts of the aforementioned aminobenzenesulfonic acid derivatives. However, the publications neither teach nor suggest that these compounds have properties to form hydrates. Furthermore, although the publications specifically disclose 2-(1-piperazinyl)-5-methylbenzenesulfonic acid in the free form (anhydrous crystal), they neither teach nor suggest as to whether or not the compound forms a monohydrate.
Generally, for the preparation of hydrates from anhydrous crystals, such methods are used, for example, (1) a method in which an anhydrous crystal is left in a steam-humidified room so as to be appropriately moistened; or (2) a method in which an anhydrous crystal is actively sprayed with humidified steam so as to be appropriately moistened. However, when large amounts of hydrates are manufactured, the above method (1) requires a prolonged period of time for humidification and it also causes difficulties that constant hydrates can hardly be manufactured, because sweat, formed in the steam room or the container, leads to partially uneven humidification. The method (2) also causes problems that constant hydrates can hardly be manufactured because of partially uneven humidification when an anhydrous crystal is insufficiently dispersed. In addition, in both of the methods (1) and (2), it is difficult to control the conditions for humidification, and accordingly, it is very likely that moisture is absorbed more than the desired amount that equates to the anhydrous crystal. In that case, a problem arises that the anhydrous crystal must be prepared all over again. The inventors of the present invention tried to prepare a monohydrate basically according to the method (1), and as described in the Reference Example which follows, they confirmed that the method had problems, for example, that the production of monohydrate required a long period of time and sweat was formed in the steam room or the container and the sweat had to be frequently wiped.